CYLD (cylindromatosis (turban tumor syndrome))
2010-05-01 Gilles Courtois AffiliationINSERM U781, Hopital Necker-Enfants Malades, Paris, France
Identity
HGNC
LOCATION
16q12.1
LOCUSID
ALIAS
BRSS,CDMT,CYLD1,CYLDI,EAC,FTDALS8,MFT,MFT1,SBS,TEM,USPL2
FUSION GENES
DNA/RNA
Figure 1. CYLD gene. Coding exons are indicated in dark red. Asterisks indicate exons which are differentially spliced. One of the exon which is alternatively present (Reiley et al., 2004) encodes the binding site for TRAF2 and NEMO (Hövelmeyer et al., 2007).
Description
21 exons (17 coding) with alternative splicing (see figure 1). Size of the exons: 74 (bp), 98, 79, 136, 626, 302, 105, 8, 98, 116, 379, 165, 141, 122, 91, 66, 132, 108, 118, 216, 5611. The whole gene extends over approximately 56 kb.
Pseudogene
No.
Proteins
Figure 2. Structural organisation of CYLD. Binding sites for TRAF2 and NEMO are indicated. CAP: CAP-Gly domain, P: phosphorylation site, C and H: subdomains of the catalytic domain containing the Cys and His active residues.
Description
956 aa, approximately 110 kD.
Member of the deubiquitinase family (USP (Ubiquitin Specific Protease)) (Reyes-Turcu et al., 2009) with preferential affinity for K63-linked polyubiquitin chains (Massoumi and Paus, 2007; Courtois, 2008).
Member of the deubiquitinase family (USP (Ubiquitin Specific Protease)) (Reyes-Turcu et al., 2009) with preferential affinity for K63-linked polyubiquitin chains (Massoumi and Paus, 2007; Courtois, 2008).
Expression
Ubiquitous.
Localisation
Cytoplasm (might bind to microtubules through its CAP-Gly domains).
Function
CYLD has been primarily identified as a negative regulator of NF-kappaB signaling, able to bind NEMO and TRAF2 and to deubiquitinate them (Brummelkamp et al., 2003; Kovalenko et al., 2003; Trompouki et al., 2003). It is also a negative regulator of JNK and p38 signaling pathways (Reiley et al., 2004) and IRF-3 signaling pathways (Friedman et al., 2008; Zhang et al., 2008). It participates in antimicrobial defense and inflammation by targeting ubiquitinated TRAF6 (Lim et al., 2007; Lim et al., 2008) and is required for the development and activation of immune cells (Reiley et al., 2006; Jin et al., 2007). CYLD may also affect cell proliferation/cell cycling by targeting Plk1 and HDAC6 (Stegmeier et al., 2007; Massoumi et al., 2009) and cell migration via microtubule assembly (Gao et al., 2008). It controls spermatogenesis by deubiquitinating RIP (Wright et al., 2007) and osteoclastogenesis by deubiquitinating TAK1 (Jin et al., 2008). A role for CYLD in the hypoxia response has been reported (An et al., 2008). Its inactivation by human papilloma virus-derived E6 protein results in hypoxia-induced NF-kappaB activation. Finally, it has been shown to affect calcium channel function by deubiquitinating TRPA1 (Stokes et al., 2006).
CYLD interacts with NEMO (Kovalenko et al., 2003; Trompouki et al., 2003), TRAF2 (Kovalenko et al., 2003; Trompouki et al., 2003), p62 (Wooten et al., 2008), Bcl-3 (Massoumi et al., 2006), TAK1 (Reiley et al., 2007), RIP (Wright et al., 2007), lck (Reiley et al., 2006), HDAC6 (Wickström et al., 2010).
CYLD interacts with NEMO (Kovalenko et al., 2003; Trompouki et al., 2003), TRAF2 (Kovalenko et al., 2003; Trompouki et al., 2003), p62 (Wooten et al., 2008), Bcl-3 (Massoumi et al., 2006), TAK1 (Reiley et al., 2007), RIP (Wright et al., 2007), lck (Reiley et al., 2006), HDAC6 (Wickström et al., 2010).
Homology
Catalytic box (with other members of the deubiquitinase family (USPs)) and CAP-Gly (with a small collection of proteins (Steinmetz and Akhmanova, 2008)).
Mutations
Figure 3. Mutations of CYLD. Misense mutations are indicated by boxes, nonsense mutations by black brackets and frameshift mutations by orange bars. Compiled from Blake and Toro, 2009 with additions from Amaro et al., 2009; Kazakov et al., 2009; Nasti et al., 2009; Wang et al., 2010 and Kazakov et al., 2010.
Germinal
Tumor suppressor (Bignell et al., 2000).
See full recent listing in Blake and Toro, 2009. Most of the mutations (non sense, frameshit, splicing) would produce large deletions of the protein but, most likely, produce mRNA nonsense-mediated decay. Short truncations affect the catalytic box which extends to the carboxy-terminus of the protein and produce an inactive enzyme. Very few missense mutations have been reported. All of them affect the catalytic box.
See full recent listing in Blake and Toro, 2009. Most of the mutations (non sense, frameshit, splicing) would produce large deletions of the protein but, most likely, produce mRNA nonsense-mediated decay. Short truncations affect the catalytic box which extends to the carboxy-terminus of the protein and produce an inactive enzyme. Very few missense mutations have been reported. All of them affect the catalytic box.
Somatic
Loss of heterozygosity in developing tumors.
Implicated in
Entity name
Familial cylindromatosis and multiple trichoepithelioma
Note
Familial cylindromatosis, also called turban tumor syndrome is a rare inherited cancer which is characterized by the formation of benign tumors, called cylindroma, in hairy parts of the body, mostly the scalp. Cylindroma are considered as originating from a transformation event specifically affecting the folliculo-sebaceous-apocrine unit that produces hair and its associated glands. Early observations established that affected patients are heterozygous at birth for the locus causing the disease, whereas the cylindroma they develop exhibit a loss of heterozygosity (LOH) demonstrating the involvment of a gene coding for a tumor suppressor. More recently, it has been shown that another genetic disease sharing similarities with familial cylindromatosis, multiple trichoepithelioma (MT), is also caused by CYLD mutations (For reviews, see Massoumi and Paus, 2007; Courtois, 2008; Amaro et al., 2009).
Entity name
Various cancers
Note
Loss of CYLD has been reported in solid tumors of the colon and liver (Hellerbrand et al., 2007), kidney (Ströbel et al., 2002), cervix (Hirai et al., 2004) and prostate (Kikuno et al., 2008). CYLD is also epigenetically silenced in some non-small-cell lung cancers (NSCLC) (Zhong et al., 2007).
In the case of melanoma, it has been shown that the CYLD promoter region is under negative control by snail, a protein which is upregulated in this disease (Massoumi et al., 2009). CYLD down-regulation results in Bcl3/NF-kappaB activation.
In the case of melanoma, it has been shown that the CYLD promoter region is under negative control by snail, a protein which is upregulated in this disease (Massoumi et al., 2009). CYLD down-regulation results in Bcl3/NF-kappaB activation.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 19929939 | 2010 | Multiple trichoepitheliomas--a novel mutation in the CYLD gene. | Amaro C et al |
| 18977328 | 2008 | Inactivation of the CYLD deubiquitinase by HPV E6 mediates hypoxia-induced NF-kappaB activation. | An J et al |
| 17692804 | 2007 | Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. | Annunziata CM et al |
| 10835629 | 2000 | Identification of the familial cylindromatosis tumour-suppressor gene. | Bignell GR et al |
| 19462465 | 2009 | Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling. | Blake PW et al |
| 12917690 | 2003 | Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. | Brummelkamp TR et al |
| 18193168 | 2008 | Tumor suppressor CYLD: negative regulation of NF-kappaB signaling and more. | Courtois G et al |
| 18636086 | 2008 | The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response. | Friedman CS et al |
| 18222923 | 2008 | The tumor suppressor CYLD regulates microtubule dynamics and plays a role in cell migration. | Gao J et al |
| 16774947 | 2007 | Reduced expression of CYLD in human colon and hepatocellular carcinomas. | Hellerbrand C et al |
| 15010838 | 2004 | Conventional and array-based comparative genomic hybridization analyses of novel cell lines harboring HPV18 from glassy cell carcinoma of the uterine cervix. | Hirai Y et al |
| 17923499 | 2007 | Regulation of B cell homeostasis and activation by the tumor suppressor gene CYLD. | Hövelmeyer N et al |
| 17609426 | 2007 | Gene mapping and expression analysis of 16q loss of heterozygosity identifies WWOX and CYLD as being important in determining clinical outcome in multiple myeloma. | Jenner MW et al |
| 18382763 | 2008 | Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice. | Jin W et al |
| 17392286 | 2007 | Deubiquitinating enzyme CYLD regulates the peripheral development and naive phenotype maintenance of B cells. | Jin W et al |
| 20132422 | 2010 | Brooke-Spiegler syndrome: report of a case with a novel mutation in the CYLD gene and different types of somatic mutations in benign and malignant tumors. | Kazakov DV et al |
| 17692805 | 2007 | Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. | Keats JJ et al |
| 18431742 | 2008 | Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells. | Kikuno N et al |
| 12917691 | 2003 | The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. | Kovalenko A et al |
| 18643924 | 2008 | CYLD is a crucial negative regulator of innate immune response in Escherichia coli pneumonia. | Lim JH et al |
| 17925880 | 2007 | Tumor suppressor CYLD acts as a negative regulator for non-typeable Haemophilus influenza-induced inflammation in the middle ear and lung of mice. | Lim JH et al |
| 19124656 | 2009 | Down-regulation of CYLD expression by Snail promotes tumor progression in malignant melanoma. | Massoumi R et al |
| 19807742 | 2009 | Five novel germline function-impairing mutations of CYLD in Italian patients with multiple cylindromas. | Nasti S et al |
| 15496400 | 2004 | Negative regulation of JNK signaling by the tumor suppressor CYLD. | Reiley W et al |
| 17548520 | 2007 | Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. | Reiley WW et al |
| 16501569 | 2006 | Regulation of T cell development by the deubiquitinating enzyme CYLD. | Reiley WW et al |
| 19489724 | 2009 | Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. | Reyes-Turcu FE et al |
| 17495026 | 2007 | The tumor suppressor CYLD regulates entry into mitosis. | Stegmeier F et al |
| 18835717 | 2008 | Capturing protein tails by CAP-Gly domains. | Steinmetz MO et al |
| 16500080 | 2006 | TRPA1 is a substrate for de-ubiquitination by the tumor suppressor CYLD. | Stokes A et al |
| 11756779 | 2002 | Spiradenocylindroma of the kidney: clinical and genetic findings suggesting a role of somatic mutation of the CYLD1 gene in the oncogenesis of an unusual renal neoplasm. | Ströbel P et al |
| 12917689 | 2003 | CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. | Trompouki E et al |
| 19911186 | 2010 | A novel missense mutation of CYLD gene in a Chinese family with multiple familial trichoepithelioma. | Wang FX et al |
| 19893491 | 2010 | CYLD negatively regulates cell-cycle progression by inactivating HDAC6 and increasing the levels of acetylated tubulin. | Wickström SA et al |
| 18174161 | 2008 | Essential role of sequestosome 1/p62 in regulating accumulation of Lys63-ubiquitinated proteins. | Wooten MW et al |
| 17981138 | 2007 | Regulation of early wave of germ cell apoptosis and spermatogenesis by deubiquitinating enzyme CYLD. | Wright A et al |
| 18467330 | 2008 | Regulation of IkappaB kinase-related kinases and antiviral responses by tumor suppressor CYLD. | Zhang M et al |
| 17043644 | 2007 | Pharmacologic inhibition of epigenetic modifications, coupled with gene expression profiling, reveals novel targets of aberrant DNA methylation and histone deacetylation in lung cancer. | Zhong S et al |
Other Information
Locus ID:
NCBI: 1540
MIM: 605018
HGNC: 2584
Ensembl: ENSG00000083799
Variants:
dbSNP: 1540
ClinVar: 1540
TCGA: ENSG00000083799
COSMIC: CYLD
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 37162682 | 2024 | YTHDC2 Retards Cell Proliferation and Triggers Apoptosis in Papillary Thyroid Cancer by Regulating CYLD-Mediated Inactivation of Akt Signaling. | 2 |
| 38246916 | 2024 | CYLD regulates cell ferroptosis through Hippo/YAP signaling in prostate cancer progression. | 1 |
| 38287022 | 2024 | CYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinoma. | 0 |
| 38319288 | 2024 | TNF and IFNγ-induced cell death requires IRF1 and ELAVL1 to promote CASP8 expression. | 0 |
| 38579060 | 2024 | Megalosplenia as an initial manifestation of multiple myeloma with a novel CYLD gene mutation: A case report and literature review. | 0 |
| 37162682 | 2024 | YTHDC2 Retards Cell Proliferation and Triggers Apoptosis in Papillary Thyroid Cancer by Regulating CYLD-Mediated Inactivation of Akt Signaling. | 2 |
| 38246916 | 2024 | CYLD regulates cell ferroptosis through Hippo/YAP signaling in prostate cancer progression. | 1 |
| 38287022 | 2024 | CYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinoma. | 0 |
| 38319288 | 2024 | TNF and IFNγ-induced cell death requires IRF1 and ELAVL1 to promote CASP8 expression. | 0 |
| 38579060 | 2024 | Megalosplenia as an initial manifestation of multiple myeloma with a novel CYLD gene mutation: A case report and literature review. | 0 |
| 36922488 | 2023 | MALT1-dependent cleavage of CYLD promotes NF-κB signaling and growth of aggressive B-cell receptor-dependent lymphomas. | 4 |
| 37176077 | 2023 | The Potential of Cylindromatosis (CYLD) as a Therapeutic Target in Oxidative Stress-Associated Pathologies: A Comprehensive Evaluation. | 3 |
| 37549179 | 2023 | CYLD stimulates macrophage phagocytosis of leukemic cells through STAT1 signalling in acute myeloid leukemia. | 0 |
| 37725175 | 2023 | Expanding CYLD protein in NF-κβ/TNF-α signaling pathway in response to Lactobacillus acidophilus in non-metastatic rectal cancer patients. | 0 |
| 37865315 | 2023 | An siRNA library screen identifies CYLD and USP34 as deubiquitinases that regulate GPCR-p38 MAPK signaling and distinct inflammatory responses. | 0 |
Citation
Gilles Courtois
CYLD (cylindromatosis (turban tumor syndrome))
Atlas Genet Cytogenet Oncol Haematol. 2010-05-01
Online version: http://atlasgeneticsoncology.org/gene/40232/cyld-(cylindromatosis-(turban-tumor-syndrome))
